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Aging-associated dysregulation of the hypoxia pathway limits skeletal muscle regeneration

衰老相关的缺氧途径失调限制了骨骼肌再生

基本信息

批准号：
10407512
负责人：
Indranil Sinha
金额：
$ 24.2万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407512
关键词：
ARNT gene Activities of Daily Living Aging American Boston Capsicum Clinical Core Grant Data Development Plans Diabetes Mellitus Doctor of Philosophy Education Elderly Exercise Exercise Physiology Exhibits Funding Genetic Transcription Gerontology Goals Hindlimb Hospital Departments Hospitals Hypertrophy Hypoxia Hypoxia Pathway Impairment Individual Individual National Research Service Award Interest Group Intervention Journals Laboratories Lead Mediating Medicine Mentors Mentorship Mus Muscle Muscular Atrophy National Institute on Aging Natural regeneration Operative Surgical Procedures Pathologic Peer Review Pharmacology Phenotype Physicians Plastic Surgical Procedures Population Prevention Program Development Proteins Protocols documentation Publications Reconstructive Surgical Procedures Recording of previous events Regenerative capacity Research Research Personnel Research Project Grants Role Secondary to Signal Pathway Signal Transduction Skeletal Muscle Testing TimeLine Training Training Programs Translating VEGFA gene Vascular Endothelial Growth Factors Wages Woman Work aged career career development education resources exercise training improved interest medical schools meetings middle age mouse model muscle aging muscle form muscle hypertrophy muscle regeneration novel novel strategies overexpression professor reduced muscle mass regeneration following injury regeneration potential research and development response restoration sarcopenia skeletal muscle differentiation skeletal muscle wasting skeletal preservation treatment strategy

项目摘要

Project Summary/Abstract This proposal describes a five-year training program and career development plan for Dr. Indranil Sinha. Dr. Sinha is a prior trainee of a National Institute of Aging-sponsored Postdoctoral Individual National Research Service Award (F32). He is a current awardee of a Research and Education Core Grant through the Boston Pepper Center and the National Institute of Aging. He has completed clinical training in Plastic and Reconstructive Surgery and is board-certified through the American Board of Plastic Surgery. He is now embarking on a research and career development program under the mentorship of Amy Wagers, Ph.D., Professor of Medicine, Harvard Medical School. Dr. Wagers is an accomplished researcher in skeletal muscle regeneration and has a history of mentoring trainees who go on to successful, independent research careers. Additional mentoring will be provided by Dr. Shalender Bhasin, a world-renowned researcher on sarcopenia, and Dr. Laurie Goodyear, an expert on exercise physiology. Dr. Sinha's career development plan includes utilization of educational resources at Brigham and Women's Hospital, Joslin Diabetes Center, and Harvard Medical School. Career development support will also be provided by the Brigham and Women's Hospital Department of Surgery, where the principle investigator will serve as an attending physician during the period of funding. Dr. Sinha has developed a clear timeline for publication of his work in peer-reviewed journals, presentations at national meetings, establishment of an Aging Interest Group within Plastic Surgery, and plans for the development of independent research projects and continued research funding. Dr. Sinha is interested in developing novel treatment strategies for aging-associated loss of skeletal muscle regeneration. He is investigating mechanisms by which aging alters hypoxia pathway signaling and skeletal muscle regenerative potential in a murine model. He found that two key factors in the hypoxia pathway, aryl hydrocarbon receptor nuclear translocator (ARNT) and vascular endothelial growth factor (VEGF), are severely dysregulated in skeletal muscle in aging and may lead to a loss of skeletal muscle regenerative potential. Furthermore, using a genetically modified mouse model, he demonstrated that muscle specific loss of ARNT recapitulates diminished skeletal muscle regeneration as associated with aging. Building on these intriguing preliminary data, the central goals of this project are to (1) mechanistically define the role of hypoxia pathway signaling and its impact on muscle regeneration in aging, (2) identify interventions to restore ARNT and VEGF signaling to preserve skeletal muscle myogenic potential, and (3) determine whether muscle hypertrophy in response to exercise, which is known to require skeletal muscle regeneration and hypoxia signaling, is limited in aging secondary to loss of ARNT.

项目摘要/摘要该提案描述了Indranil博士的五年培训计划和职业发展计划辛哈。辛哈博士是国家老龄研究所资助的博士后个人国立大学的高级实习生研究服务奖(F32)。他现为研究及教育核心资助金获得者。波士顿胡椒中心和国家老龄研究所。他已经完成了整形和临床培训重建外科，并通过美国整形外科委员会的董事会认证。他现在是在艾米·韦杰斯博士的指导下开始研究和职业发展计划，哈佛医学院医学教授。韦杰斯博士是一位在骨骼肌领域颇有成就的研究员。并有指导学员走向成功的独立研究职业生涯的历史。其他指导将由世界著名的石棺减少症研究人员沙伦德·巴辛博士提供。以及运动生理学专家劳里·古德伊尔博士。辛哈博士的职业发展计划包括布里格姆妇女医院、乔斯林糖尿病中心和哈佛大学的教育资源利用情况医学院。布里格姆妇女医院还将提供职业发展支助。外科，在此期间，首席调查员将担任主治医生资金的问题。辛哈博士制定了在同行评议期刊上发表他的研究成果的明确时间表，在全国会议上的介绍，在整形外科领域内成立老龄问题小组，以及计划用于独立研究项目的开发和继续研究的资金。辛哈博士对开发与衰老相关的骨骼丢失的新治疗策略感兴趣肌肉再生。他正在研究衰老改变缺氧信号通路和小鼠模型中的骨骼肌再生潜力。他发现低氧的两个关键因素芳烃受体核转运体与血管内皮生长因子途径 (血管内皮生长因子)，在骨骼肌衰老过程中严重失调，并可能导致骨骼肌丧失再生潜力。此外，使用转基因小鼠模型，他展示了肌肉 ARNT的特异性丢失重述了骨骼肌再生与衰老相关的减少。建房根据这些耐人寻味的初步数据，该项目的中心目标是(1)机械地定义缺氧信号通路及其对衰老肌肉再生的影响，(2)确定恢复的干预措施 ARNT和血管内皮生长因子信号转导以保护骨骼肌的生肌潜能，以及(3)决定肌肉是否运动引起的肥大，已知需要骨骼肌再生和低氧信号转导，仅限于继发于ARNT缺失的衰老。